HDAC6 is a bruchpilot deacetylase that facilitates neurotransmitter release

Miskiewicz K.;Jose L. E.;Yeshaw W. M.;Valadas J. S.;Swerts J.;Munck S.;Feiguin F.;Dermaut B.;Verstreken P.

2014-01-01

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Abstract

Presynaptic densities are specialized structures involved in synaptic vesicle tethering and neurotransmission; however, the mechanisms regulating their function remain understudied. In Drosophila, Bruchpilot is a major constituent of the presynaptic density that tethers vesicles. Here, we show that HDAC6 is necessary and sufficient for deacetylation of Bruchpilot. HDAC6 expression is also controlled by TDP-43, an RNA-binding protein deregulated in amyotrophic lateral sclerosis (ALS). Animals expressing TDP-43 harboring pathogenic mutations show increased HDAC6 expression, decreased Bruchpilot acetylation, larger vesicle-tethering sites, and increased neurotransmission, defects similar to those seen upon expression of HDAC6 and opposite to hdac6 null mutants. Consequently, reduced levels of HDAC6 or increased levels of ELP3, a Bruchpilot acetyltransferase, rescue the presynaptic density defects in TDP-43-expressing flies as well as the decreased adult locomotion. Our work identifies HDAC6 as aBruchpilot deacetylase and indicates that regulatingacetylation of a presynaptic release-site protein is critical for maintaining normal neurotransmission. © 2014 The Authors.